Tolerance to ethanol is a multifaceted phenomenon, with different types of tolerance resulting from different paradigms of administration of the drug. Recently, a conditioning model for the development of tolerance has received attention. A conditioning model, as well as an environment-independent, liquid diet technique for development tolerance will be established for several inbred strains of mice, so that various aspects of tolerance can be compared, i.e., rate of development, extent, rate of dissipation, dose parameters, situation specificity, response specificity, influence of peptides, and involvement of metabolic/dispositional alterations. These studies should enhance the understanding of tolerance by delineating the critical features determining and resulting from the development of different types of tolerance. Indications of involvement of different neurochemical systems in the conditioning model will be investigated by testing for cross-tolerance. Tolerance to the hypothermic effects of ethanol will be produced, then the animals will be tested for cross-tolerance to agonists of various systems which influence body temperature. An attempt will also be made to develop tolerance to various compounds and test for cross-tolerance to ethanol. Since tolerance is an integral part of definitions of alcoholism, the information gained in exploring tolerance will be used to assess the hypothesis that tetrahydroisoquinolines (TIQs) may be involved in alcoholism, by examining the influence of administering selected TIQs on different types of tolerance. With further understanding of the phenomenon of tolerance, these studies will also provide further information on the action of TIQs as pharmacological tools.